Hsp90 inhibition results in autophagy-mediated proteasome-independent degradation of IkappaB kinase (IKK)

Cell Res. 2006 Nov;16(11):895-901. doi: 10.1038/sj.cr.7310109.


Autophagic and proteasomal proteolysis are two major pathways for degradation of cellular constituents. Current models suggest that autophagy is responsible for the nonselective bulk degradation of long-lived proteins and organelles while the proteasome specifically degrades short-lived proteins including misfolded proteins caused by the absence of Hsp90 function. Here, we show that the IkappaB kinase (IKK), an essential activator of NF-kappaB, is selectively degraded by autophagy when Hsp90 is inhibited by geldanamycin (GA), a specific Hsp90 inhibitor showing highly effective anti-tumor activity. We find that in this case inactivation of ubiquitination or proteasome fails to block IKK degradation. However, inhibition of autophagy by an autophagy inhibitor or knockout of Atg5, a key component of the autophagy pathway, significantly rescues IKK from GA-induced degradation. These findings provide the first evidence that an Hsp90 client may be degraded by a mechanism different from the proteasome pathway and establish a molecular link among Hsp90, NF-kappaB and autophagy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / drug effects
  • Autophagy / physiology*
  • Benzoquinones / pharmacology
  • Cell Line
  • Cells, Cultured
  • Gene Expression / drug effects
  • Gene Expression / genetics
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • HSP90 Heat-Shock Proteins / metabolism
  • HSP90 Heat-Shock Proteins / physiology
  • HeLa Cells
  • Humans
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism*
  • I-kappa B Proteins / metabolism
  • Immunoblotting
  • Lactams, Macrocyclic / pharmacology
  • Mice
  • Models, Biological
  • Polymerase Chain Reaction
  • Proteasome Endopeptidase Complex / metabolism*
  • Signal Transduction / drug effects
  • Ubiquitin / metabolism


  • Benzoquinones
  • HSP90 Heat-Shock Proteins
  • I-kappa B Proteins
  • Lactams, Macrocyclic
  • Ubiquitin
  • I-kappa B Kinase
  • Proteasome Endopeptidase Complex
  • geldanamycin